Butyrate Suppresses Glucose Metabolism of Colorectal Cancer Cells via GPR109a-AKT Signaling Pathway and Enhances Chemotherapy.

Glycolysis inhibitors are promising therapeutic drugs for tumor treatment, which target the uniquely elevated glucose metabolism of cancer cells. Butyrate is a critical product of beneficial microbes in the colon, which exerts extraordinary anti-cancer activities. In particular, butyrate shows biased inhibitory effects on the cell growth of cancerous colonocytes, whereas it is the major energy source for normal colonocytes. Besides its roles as the histone deacetylases (HDACs) inhibitor and the ligand for G-protein coupled receptor (GPR) 109a, the influence of butyrate on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully understood. Here, we show that butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells, through reducing the abundance of membrane GLUT1 and cytoplasmic G6PD, which was regulated by the GPR109a-AKT signaling pathway. Moreover, butyrate significantly promoted the chemotherapeutical efficacy of 5-fluorouracil (5-FU) on cancerous colonocytes, with exacerbated impairment of DNA synthesis efficiency. Our findings provide useful information to better understand the molecular basis for the impact of butyrate on the glucose metabolism of colorectal cancer cells, which would promote the development of beneficial metabolites of gut microbiota as therapeutical or adjuvant anti-cancer drugs.

Physicochemical properties and cell-based bioactivity of Pu'erh tea polysaccharide conjugates.

Polysaccharide conjugates were prepared from Pu'erh tea and fractionated by DEAE-cellulose DE-52 column chromatography to yield one unexplored polysaccharide-conjugate fraction termed TPC-P with a molecular weight of 251,200Da. DVS (dynamic vapour sorption) result discovered that the humidity condition of long-term preservation for TPC-P is below 70% RH. Although it contained proteins, TPC-P could not bind to the Coomassie Brilliant Blue dyes G250 and R250. The "shoulder-shaped" ultroviolet absorption peak in TPC-P UV-vis scanning spectum ascribe theabrownins that inevitably adsorbed the polysaccharide conjugate. Zeta potential results demonstrated TPC-P aqueous solution merely presented the negative charge properties of polysaccharides instead of acid-base property of its protein section, and had more stability in greater than pH 5.5. No precipitation or haze occurred in the three TPC-P/EGCG aqueous mixtures during their being stored for 12h. The phase separation was observed in aqueous mixtures of TPC-P and type B gelatin. TPC-P possessed the fine stability as a function of temperature heating and cooling between 0 and 55°C. It is proposed that some properties of the covalent binding protein of TPC-P were "shielded" by its polysaccharide chains.

Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord.

Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, neuropathic pain is one of the main limiting complications of OXL. The purpose of this study was to examine the underlying mechanisms by which neuropathic pain is induced by OXL in a rat model. Our results demonstrated that blocking spinal proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) attenuated pain responses evoked by mechanical stimulation and decreased the releases of substance P and CGRP in the superficial dorsal horn of the spinal cord. The attenuating effect on mechanical pain was significantly smaller in OXL-rats than that in control rats. Blocking PAR2 also attenuated a heightened cold sensitivity evoked by OXL; whereas blocking TRPV1 had little effects on OXL-evoked hypersensitive cold response. Our data also showed that OXL increased the protein expressions of PAR2 and TRPV1 in the superficial dorsal horn. In addition, blocking PAR2 decreased TRPV1 expression in OXL-rats. Overall, our data suggest that upregulated expression of PAR2 in the superficial dorsal horn contributes to mechanical hyperalgesia and cold hypersensitivity; whereas amplified TRPV1 plays a role in regulating mechanical hyperalgesia, but not cold hypersensitivity after administration of OXL. We further suggest that TRPV1 is likely one of the signaling pathways for PAR2 to play a role in regulating OXL-induced neuropathic pain.

Reduced T-cadherin expression and promoter methylation are associated with the development and progression of hepatocellular carcinoma.

Loss of T-cadherin expression has been reported in a number of human cancers. We previously reported that T-cadherin re-expression suppressed cell growth and motility in glioma. Here, we report that the T-cadherin expression was significantly decreased in human hepatocellular carcinoma (HCC) compared to adjacent normal liver. In addition, T-cadherin expression in HCC with metastasis was significantly lower than in HCC without metastasis. To determine the mechanism underlying the reduced T-cadherin expression in HCC, we examined T-cadherin promoter methylation. We found that methylation of the T-cadherin promoter was present in 40% of HCC, but absent in all adjacent liver tissues. In the HCC with T-cadherin promoter methylation, the T-cadherin expression was significantly decreased compared to HCC without methylation. To provide a functional link between T-cadherin promoter methylation and T-cadherin growth regulation, we used the HepG2 hepatoma cell line that exhibits T-cadherin promoter methylation. Treatment of HepG2 cells with the demethylating agent 5-aza-2-deoxycytidine resulted in increased T-cadherin expression and reduced cell proliferation. These results demonstrate that the T-cadherin down-regulation by promoter methylation is associated with the development and progression of HCC, and suggest that T-cadherin is an important tumor suppressor in liver cancer.